VCV000060510.13 - ClinVar

NM_021942.6(TRAPPC11):c.2938G>A (p.Gly980Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_021942.6(TRAPPC11):c.2938G>A (p.Gly980Arg)

Variation ID: 60510 Accession: VCV000060510.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q35.1 4: 183701783 (GRCh38) [ NCBI UCSC ] 4: 184622936 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 18, 2016	Apr 6, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_021942.6:c.2938G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_068761.4:p.Gly980Arg	missense
NM_199053.3:c.2938G>A	NP_951008.1:p.Gly980Arg	missense
NC_000004.12:g.183701783G>A
NC_000004.11:g.184622936G>A
NG_033102.1:g.47517G>A
	Q7Z392:p.Gly980Arg

... more HGVS ... less HGVS

Protein change

G980R

Other names

Canonical SPDI

NC_000004.12:183701782:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00007

Links

ClinGen: CA144539 UniProtKB: Q7Z392#VAR_070158 OMIM: 614138.0001 dbSNP: rs397509417 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TRAPPC11		-	-	GRCh38 GRCh37	874	1061

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive limb-girdle muscular dystrophy type R18	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000054408.20

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type R18 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581874.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4_MOD, PM3, PM2_SUP, PP1, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type R18 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807243.2 First in ClinVar: Nov 18, 2016 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 23830518 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 1-year-old female with motor delays, hypotonia, elevated … (more) This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 1-year-old female with motor delays, hypotonia, elevated CK and transaminases. (less)
Pathogenic (Nov 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type R18 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000945321.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23830518‚ 26322222‚ 26912795 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 980 of the TRAPPC11 protein (p.Gly980Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 980 of the TRAPPC11 protein (p.Gly980Arg). This variant is present in population databases (rs397509417, gnomAD 0.08%). This missense change has been observed in individual(s) with TRAPPC11-related conditions (PMID: 23830518, 26322222; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60510). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRAPPC11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRAPPC11 function (PMID: 23830518, 26912795). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal recessive limb-girdle muscular dystrophy type R18 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801266.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Pathogenic (Jul 11, 2013)	no assertion criteria provided Method: literature only	MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 18 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000082885.4 First in ClinVar: Aug 04, 2013 Last updated: Sep 28, 2018	Publications: PubMed (3) PubMed: 23830518‚ 26322222‚ 26912795 Comment on evidence: In affected members of a consanguineous Syrian family with autosomal recessive limb-girdle muscular dystrophy type 2S (LGMDR18; 615356), Bogershausen et al. (2013) identified a homozygous … (more) In affected members of a consanguineous Syrian family with autosomal recessive limb-girdle muscular dystrophy type 2S (LGMDR18; 615356), Bogershausen et al. (2013) identified a homozygous c.2938G-A transition in the TRAPPC11 gene, resulting in a gly980-to-arg (G980R) substitution at a highly conserved residue in the gryzun domain. The mutation was found by exome sequencing combined with linkage analysis and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in several large control databases or in 100 Turkish controls. Studies of patient cells indicated an intracellular trafficking defect. In an 8-year-old Han Chinese girl with a variant of LGMDR18, Liang et al. (2015) identified compound heterozygous mutations in the TRAPPC11 gene: G980R and a splice site mutation (c.661-1G-T; 614138.0003). The mutations, which were found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In addition to muscular dystrophy, the patient had delayed psychomotor development with borderline cognitive function, infantile-onset cataracts, and hepatic steatosis. DeRossi et al. (2016) found that patient fibroblasts with the G980R mutation showed abnormal accumulation of lipid droplets. (less)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 980 of the TRAPPC11 protein (p.Gly980Arg). This variant is present in population databases (rs397509417, gnomAD 0.08%). This missense change has been observed in individual(s) with TRAPPC11-related conditions (PMID: 23830518, 26322222; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 60510). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRAPPC11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRAPPC11 function (PMID: 23830518, 26912795). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
trappc11 is required for protein glycosylation in zebrafish and humans.	DeRossi C	Molecular biology of the cell	2016	PMID: 26912795
Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype.	Liang WC	Skeletal muscle	2015	PMID: 26322222
Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.	Bögershausen N	American journal of human genetics	2013	PMID: 23830518

Text-mined citations for rs397509417 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_021942.6(TRAPPC11):c.2938G>A (p.Gly980Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397509417 ...